Competitive Endogenous Role of the LINC00511/miR-185-3p Axis and miR-301a-3p From Liquid Biopsy as Molecular Markers for Breast Cancer Diagnosis

Abstract

Breast cancer (BC) is the leading cause of female cancer-related mortalities. Evidence has illustrated the role of long non-coding RNAs (lncRNA) and microRNAs (miRNA) as promising pool of protein non-coding regulators, for tuning the aggressiveness of several malignancies. This research aims to unravel the expression pattern and the emphases of the diagnostic value of the long intergenic ncRNA00511 (LINC00511) and its downstream microRNA (miR-185-3p) and the pathogenic significance of the onco-miR-301a-3p in naïve BC patients. LINC00511 was chosen and validated, and its molecular binding was confirmed using bioinformatics. LINC00511 was measured in 25 controls and 70 patients using qPCR. The association between the investigated ncRNA’s expression and the BC patients’ clinicopathological features was assessed. Receiver operating characteristic (ROC) curve was blotted to weigh out their diagnostic efficacy over the classical tumor markers (TMs). Bioinformatics and Spearman correlation were used to predict the interaction between LINC00511, miR-185-3p, and miR-301a-3p altogether to patients’ features. LINC00511 and miR-301a-3p, in BC patients’ blood, were overexpressed, and their median levels increased significantly, while miR-185-3p was, in contrast, downregulated, being decreased fourfold. LINC00511 was elevated in BC early stages, when compared to late stages (p < 0.0003). LINC00511, miR-185-3p, and miR-301a-3p showed AUC superior to classical TMs, allowing us to conclude that the investigated ncRNAs, in BC patients’ liquid biopsy, are novel diagnostic molecular biomarker signatures. Lymph node metastasis (LNM) and advanced tumor grade were directly correlated with LINC00511 significantly. Additionally, both LINC00511 and miR-301a-3p were positively correlated with the aggressiveness of BC, as manifested in patients with larger tumors (>2 cm) at (p < 0.001). Therefore, these findings aid our understanding of BC pathogenesis, in the clinical setting, being related in part to the LINC00511/miR axis, which could be a future potential therapeutic target.

Cancer Biomarkers in Liquid Biopsy for Early Detection of Breast Cancer: A Systematic Review

“…In total, 16 142 articles were identified in the aforementioned databases (Table 1). However, 234 articles were retained for full reading, following the elimination of duplicates and articles whose title and abstract did not meet the eligibility criteria; of these, only 136 12…”

“…Abbreviations: BC, breast cancer; HER2, human epidermal growth factor 2; LB, liquid biopsy. As shown in Table 6, highlighted in gray, 28 biomarkers presenting a Sensitivity greater than 90% were identified: miR-17-5p, miR-155, miR-222, 89 miR-202, 60 PTEN, SMAD4, 24 APC, RARB2, 115 miRNA-222, miRNA-373, 92 miR-27a, 85 cfDNA methylation score, 25 HER2 mRNA, 95 miR-21, 28 polymorphism -31G/C in survivin promoter gene, 79 hsa-miR25-3p, hsa-miR-548ar-5p, 80 miR-598-3p, miR-1246, 105 miR-495, 117 telomeric sequences in cfDNA, 121 miR-30c, miR-148a, 39 miR-185-3p, 49 miR-34a, 17 miR10b, miR21, 12 and miRNA-373. 34 As shown in Table 7, highlighted in gray, 16 biomarker panels in peripheral blood can be observed 19,22,27,29,30,42,44,54,61,81,93,98,106,111,112,123 and 2 biomarker panels in saliva 74,86 with a sensitivity greater than 90%.…”

The double agents in liquid biopsy: promoter and informant biomarkers of early metastases in breast cancer

“…Long non-coding RNA LINC00511 and onco-miR-301a-3p are found to be significantly overexpressed in early stage BC patients’ liquid biopsy samples and in patients with larger tumors (> 2 cm) as compared to later stages [ 92 ]. LINC00511 is also directly correlated with aggressiveness marked by Lymph node metastasis (LNM) and advanced tumor grade, whereas its downstream miRNA, miR-185-3p displayed a fourfold downregulated expression highlighting an independent mechanism of action suggesting that lncRNAs:miRNAs may also be utilized as tumor biomarkers in blood [ 93 ].…”

Notch-associated lncRNAs profiling circuiting epigenetic modification in colorectal cancer

“…LncRNAs can act as post-transcriptional regulators, including competitive endogenous RNA (ceRNA) acting as sponge for miRNAs and hence, silencing its target mRNA [ 58 ] or lncRNAs-mRNA direct interaction via recognizing complimentary sequences, with an overall regulation of capping, splicing and mRNA stability [ 54 ], Fig. 2 C.…”